Many biological interactions are mediated by binding between a multivalent receptor and its target. Such multivalent binding occurs between virus receptors and ligands expressed at the surface of target cells prior to infection.
Antibodies (IgG, IgM) bind antigen via multiple binding sites prior to initiation of the complement cascade (Alzari et al (1988); Merritt and Hol (1995); Ascenzi et al (2000); Reni (1995)).
The events that occur subsequent to the initial multivalent binding event (e.g. viral infection of cells, transfusion/tissue rejection) are often deleterious to the host.
Multivalent binding events are characterized by low dissociation constants (Kd). A compound intended to be administered to a host as a competitive inhibitor of the binding event must have a significantly higher affinity for the receptor to provide a therapeutic effect.
One approach to providing competitive inhibitors of multivalent binding is to design compounds comprising multiple ligands for the receptor.
Dendrimeric molecules are an example of compounds comprising multiple ligands designed to participate in multivalent binding with a receptor (Tomalia et al (1990); Tsvetkov et al (2002); Jayaraman et al (1997)).
A limitation of these dendrimeric molecules is that they are of high molecular weight and the intramolecular ligand separation is poorly defined.
A further limitation of these dendrimeric molecules is that many of the ligands of the molecule do not participate in productive interactions with the receptor.
Antennary molecules are another example of compounds comprising multiple ligands designed to participate in multivalent binding with a receptor (Fon et al (2000)).
An advantage of antennary molecules is that they comprise fewer ligands—typically three to five—than their dendrimeric counterparts.
The use of rigid carrier molecules or templates is yet another example of the design of compounds comprising multiple ligands for a receptor.
Candidate carrier molecules include cyclodextrins, calixarenes and porphirines (Kiessling and Pohl (1996); Matsuura et al (2004); Mellet et al (2002); Lundquist and Toone (2002); Fon et al (2000)).
A limitation of these rigid carrier molecules is that their dimensions place a constraint on the possible intra-molecular separation of the conjugated ligands (circa 10 Å).
The dimensions of carrier molecules is in contrast with the separation of the binding sites of multivalent receptors such as viruses (e.g. influenza virus hemaglutinin (HA) >50 Å) and antibodies (>100 Å).
It is an object of the invention to provide molecules capable of inhibiting multivalent binding events.
It is an object of the invention to provide a method of preparing inhibitors of the interaction between a multivalent receptor and its target where the intra-molecular separation of the ligands is pre-determined.
These objects are to be read disjunctively with the object of to at least provide a useful choice.